The Neurocritic

Thursday, March 31, 2016

New in the journal journal Cortex: four shocking cases of practicing medicine while exhausted (Dharia & Zeman, 2016). The authors called this newly discovered syndrome “fatigue amnesia.” Why this is is any different from countless other examples of not remembering things you did while exhausted — I do not know. Except amnesia for performing a complex medical procedure is a lot more disturbing than forgetting you did the dishes the night before.

Here are the cases in brief:

Case 1: A consultant geriatrician, while working as house officer, treated a patient with chest pain and severe pulmonary oedema in the middle of night. She made an entry in the notes, demonstrating successful initial memory acquisition. She does not remember going to bed that night. On the ward round on the following morning the patient was pointed out to her but she had no recollection of seeing the patient or writing the note.

Case 2: A senior house officer, now a consultant neurologist, went to bed in the early hours after a busy shift. She was woken soon afterwards to manage a patient with cardiac arrest. The resuscitation was complex and included an intracardiac adrenaline injection. She documented events in the medical notes immediately, demonstrating successful initial memory acquisition. She returned to bed. She was told on the morning ward round that the patient was well and had his breakfast following the cardiac arrest. She was startled by this information, as she had no recollection of the previous night's events.

Case 3: A consultant microbiologist who was working on a night shift as a house officer clerked in a patient at 11:00 pm and continued to work thereafter throughout the night. On the morning ward round when the patient was pointed out to her she had no recollection of seeing or managing him.

Case 4: A paediatrician reported memory loss for a complex decision made and instructions given over the phone. While working as a registrar he went to bed in the early hours of morning when on call. He was woken by a call about a complex patient. He went to the ward soon afterwards to find out that the trolley was laid out for Swan Ganz catheterisation. Although he was assured that he had done so, he did not remember giving instructions to prepare the trolley.

The incidents were not due to alcohol or drugs. Long hours and sleep deprivation were to blame. And fortunately, the amnesic episodes were isolated and did not recur in any of the doctors. Dharia & Zeman (2016) suggested that:

While the resulting memory gaps can reasonably be described as resulting from a ‘transient amnesic state', the evidence from the medical notes suggest that this phenomenon reflects a novel form of accelerated long-term forgetting (Elliott, Isaac, & Muhlert, 2014), whereby a memory for events is acquired normally but then decays more rapidly than usual.

Sometimes the press coverage of a snappy dopamine paper can be positive and (mostly) accurate, as was the case with a recent paper on risk aversion in rats (Zalocusky et al., 2016). This study showed that rats who like to “gamble” on getting a larger sucrose reward have a weaker neural response after “losing.” In this case, losing means choosing the risky lever, which dispenses a low amount of sucrose 75% of the time (but a high amount 25%), and getting a tiny reward. The gambling rats will continue to choose the risky lever after losing. Other rats are risk-averse, and will choose the “safe” lever with a constant reward after losing.

This paper was a technical tour de force with 14 multi-panel figures.1 For starters, cells in the nucleus accumbens (a VTA target) expressing the D2 receptor (NAc D2R+ cells) were modified to express a calcium indicator that allowed the imaging of neural activity (via fiber photometry). Activity in NAc D2R+ cells was greater after loss, and during the decision phase of post-loss trials. And these two types of signals were dissociable.2 Then optogenetic methods were used to activate NAc D2R+ cells on post-loss trials in the risky rats. This manipulation caused them to choose the safer option.

More surprising are two recent papers in the highly sought-after population of humans implanted with electrodes for seizure monitoring or treatment of Parkinson's disease. I'll leave you with quotes from these papers as food for thought.

1. Stenner et al. (2015). No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation.

The next one is extremely impressive for combining deep brain stimulation with fast-scan cyclic voltammetry, a method that tracks dopamine fluctuations in the human brain!

Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

Further Reading

As Addictive As Cupcakes– Mind Hacks (“If I read the phrase ‘as addictive as cocaine’ one more time I’m going to hit the bottle.”)

Sunday, March 20, 2016

Our bodily sense of self contributes to our personal feelings of awareness as a conscious being. How we see our bodies and move through space and feel touched by loved ones are integral parts of our identity. What happens when this sense of self breaks down? One form of dissolution is Depersonalization Disorder (DPD).1 Individuals with DPD feel estranged or disconnected from themselves, as if their bodies belong to someone else, and “they” are merely a detached observer. Or the self feels absent entirely. Other symptoms of depersonalization include emotional blunting, out-of-body experiences, and autoscopy.

Transient symptoms of depersonalization can occur due to stress, anxiety, sleep deprivation, or drugs such as ketamine (a dissociative anesthetic) and hallucinogens (e.g., LSD, psilocybin). These experiences are much more common than the official diagnosis of DPD, which occurs in only 1-2% of the population.

Research by Olaf Blanke and colleagues (reviewed in Blanke et al., 2015) has tied bodily self-consciousness to the integration of multi-sensory signals in fronto-parietal and temporo-parietal regions of the brain.

The fragmentation or loss of an embodied self raises philosophically profound questions. Although the idea of “mind uploading” is preposterous in my view (whether via whole brain emulation or cryonics), proponents must seriously ask whether the uploaded consciousness will in any way resemble the living person from whom it arose.2 “Minds are not disembodied logical reasoning devices” (according to Andy Clark). And...

Increasing evidence suggests that the basic foundations of the self lie in the brain systems that represent the body (Lenggenhager et al., 2012).

Lenggenhager et al. asked whether the loss of sensorimotor function alters body ownership and the sense of self. Persons with spinal cord injuries scored higher on Cambridge Depersonalization Scale (CDS) items such as “I have to touch myself to make sure that I have a body or a real existence.” This suggests that disconnecting the brain from somatosensory input can change phenomenological aspects of self-consciousness.

Patients with depersonalization not only feel a change in perception concerning the outside world, but they also have clear-cut changes concerning their own body. ... The patient sees his face in the mirror changed, rigid and distorted. His own voice seems strange and unfamiliar to him. ... It is in this respect especially remarkable that the estrangement concerning the outside world is often an estrangement in the optic sphere (Schilder, 1935, p. 139).

Depersonalization can involve perceptual distortions of bodily experience in different sensory modalities (e.g., vision, hearing, touch, and pain). Recent research has examined interactions between visual and somatosensory representations of self in the tactile mirroring paradigm (also called visual remapping of touch). Here, the participant views images of a person being touched (or not) while they themselves are touched. Tactile perception is enhanced by simultaneously receiving and observing the same stimulation, especially when the image is of oneself.

Are the symptoms of depersonalization associated with reduced or absent responses in the tactile mirroring paradigm? If so, at what stage of processing (early or late) does this occur? A new study recorded EEG to look at somatosensory evoked potential (SEP) responses to tactile stimuli during mirroring (Adler et al., 2016). The participants scored high (n=14) or low (n=13) on the CDS.

One SEP of interest was the P45, which occurs shortly (25-50 msec) after tactile stimulation. Although the spatial resolution of EEG does not allow firm conclusions about the neural generators, we know from invasive studies in epilepsy patients and animals that P45 originates in the primary somatosensory cortex (S1).

When the participants viewed the other-face, P45 did not differ on touch vs. no-touch trials. But the later N80 component was enhanced for touch vs. no-touch, and the enhancement was similar for low and high depersonalization (DP) participants.

Modified from Figs. 3 and 4 (Adler et al. 2016). SEPs in response to tactile stimuli for low DP (top) and high DP (bottom) while observing touch (thick line) or no-touch (thin line) on another person's face. SEPs are shown for components P45 and N80 at a cluster of central-parietal electrodes located over somatosensory cortex.

Results were different when subjects viewed images of themselves. P45 was enhanced in the low DP group when viewing themselves being touched (vs. no-touch trials). However, those with high DP scores did not show this P45 enhancement.

These results suggest a very early disturbance in sensory integration of the self in depersonalization:

Measurable effects of mirroring for tactile events on the observer's own face may be absent over P45 because deficits in implicit self-related processing prevent the resulting visual enhancement of tactile processing from taking place in the context of self-related information. An alternative, or additional, explanation for the absence of P45 mirroring effects may be that seeing their own body causes depersonalised individuals to actively inhibit the processing of bodily stimulation via this pathway. This may cause feelings of disembodiment, and is akin to the suggestion that fronto-limbic inhibitory mechanisms acting on emotional processes cause the emotional numbing experienced in depersonalisation (Sierra and David, 2011).

[Although I'm not so sure how much “active inhibition” can occur within 25 msec...]

A later component (P200) did not show the expected effect in the high DP group, either. While these results are intriguing, we must keep in mind that this was a small study that requires replication.3

Our Bodies, Our Selves

Predictive coding models hypothesize that the anterior insular cortex (AIC) provides top-down input to somatosensory, autonomic, and visceral regions and plays a critical role in integrating exteroceptive and interoceptive signals (Seth et al., 2012; Allen et al., 2016). DPD is associated with “pathologically imprecise interoceptive predictive signals,” leading to a disruption of conscious presence (the subjective sense of reality of the world and of the self within the world). Here's the predictive coding model of conscious presence (Seth et al., 2012):

It has been suggested that DPD is associated with a suppressive mechanism grounded in fronto-limbic brain regions, notably the AIC, which “manifests subjectively as emotional numbing, and disables the process by which perception and cognition become emotionally colored, giving rise to a subjective feeling of unreality” (Sierra and David, 2011)...

In our model, DPD symptoms correspond to abnormal interoceptive predictive coding dynamics. ... the imprecise interoceptive prediction signals associated with DPD may result in hypoactivation of AIC since there is an excessive but undifferentiated suppression of error signals.

We speculate that the abnormalities related to depersonalisation may be based on a lack of mirroring interactions in early childhood. Several recent papers culminated in the idea that mirroring experiences in early life - the process of moving and being moved by others, both physically and affectively - give rise to our sense of bodily self... This bodily self forms the core of other forms of self-consciousness, from body ownership to the sense of agency and the ability to mentalise (e.g. Fonagy et al., 2007; Gallese & Sinigaglia, 2010; Markova and Legerstee, 2006; Stern, 1995). ... Depersonalisation could be a potential consequence of such developmental experiences.

I don't buy it... none of the participants in their study had a clinical diagnosis, and we know nothing of their early childhood. In the end, any model of chronic DPD still has to account for the transient phenomena of disconnection and unreality experienced by so many of us.

Monday, March 07, 2016

Who is this, wandering around the crowded street, afraid of everything, trusting no one? “There must be something wrong, somewhere.”But maybe I’m safer since I look disheveled. Who are these people? Where is this place?Did I write that? When did that happen? I don’t remember.I can’t stop writing. I can’t stop walking, either, which is a problem because it’s hard to write and walk at the same time.

THE peculiar condition designated “fugue state,” of which the main symptom is compulsive wandering, has puzzled psychiatrists since it was first described. Nothing is known of the aetiology of this well-defined condition. Fugue states occur in epileptics, hysterics, and certain psychopaths. Bleuler has described their occurrence in schizophrenia, and they have been recorded in cases of general paralysis and of altered personality due to brain tumour. ... Kraepelin recognized that it was impossible to distinguish between the states of compulsive wandering associated with various mental disorders. Janet tried to distinguish between hysterical and epileptic fugues by pointing out that short fugues are more likely to be epileptic than hysterical.

He was disturbed by inaccurate use of the term, which was widespread (Stengel, 1943):

...the following conditions have been described as fugues: States of wandering, in accordance with the classical conception; states of double personality; all kinds of transitory abnormal behaviour of functional origin; hysterical loss of consciousness and of memory; twilight states; confusional states of hysterical nature; delirious states in schizophrenia. The tendency to call transient states of altered consciousness fugues, irrespective of the behaviour of the patient, is obvious. This is a most unsatisfactory state of affairs.

Stengel presented dozens of cases in these papers and was obsessed with finding common etiological factors, no matter what the underlying medical condition (e.g., epilepsy, “hysteria”, schizophrenia):

The intimate similarity of fugue states associated with different mental disorders suggests that there must be aetiological factors common to all. However, no attempt has been made hitherto to ascertain such factors. I have been engaged in investigations concerning this problem for more than eight years...

Clinical studies carried out over many years have convinced me that there is no justification in differentiating between hysterical and epileptic wandering states, as the behaviour of the patients and the majority of the etiological factors are fundamentally the same in all fugues with the impulse to wander (Stengel, 1939, 1941).

Since Stengel was trained as a psychoanalyst and considered Freud as a mentor, you might guess the common etiology:

This was a disturbance of the environment of child life. A serious disturbance in the child-parent relationship, usually of such a nature that the relationship to one or both parents was either completely lacking or only partially developed, had occurred in nearly every case.

CASE 9. — M. E —, female, born 1906. The patient was normal until her twenty first year. At that time she suddenly became unstable and wanted to live apart from her mother, with whom she had been happy hitherto. She went to Paris, where she found employment as a secretary, but after some months she returned home again. When she was 22 she experienced for the first time an urge to wander, which reappeared subsequently two or three times every year. For no adequate reason, sometimes after an insignificant quarrel, she left home and wandered about for some days. During these states she was not fully conscious, slept little, and neglected herself. When normal consciousness returned, after three or four days, she found herself in the country far away from home. These states were followed by profound depression, lasting for several weeks, when the patient indulged in self-reproaches, ate very little, lost weight, and could not work. ... The patient was a typical daydreamer. In her daydreams a fantasy of a man disappointed in love committing suicide often appeared. (Her father had committed suicide.) ... The patient, who was of unusual intelligence, suffered very much from her abnormal states, which appeared at intervals of four to five months, and were always followed by melancholic depression. In one of these depressions she committed suicide by poisoning.

Period Fugue

Stengel (1941) asserted that the majority of his female patients started their wandering premenstrually, but his definition of what this meant was kind of loose (and meaningless): “usually appear before menstruation”, “usually just before menstruation”, “usually commences shortly before her menstrual period”, “at the onset of menstruation”, “about the time of menstruation”.

He had no explanation for this, other than the implication that it's an unstable lady thing. One particularly fun case (Case 14) was a young woman with a previous bout of encephalitis lethargica. But it was determined that her menstrual period and an Oedipus Complex drove her to wander, not her illness.

The report for Case 35 (Miss May S. M—, aged 18, member of the women's military service) was accompanied by a four page excerpt from her diary, which is illuminating for what it tells us about bipolar disorder (but fugue, not so much):

“ 1940. 12.1: Had a drink, sang all the way home. —13.1: The matinee went off well. Feeling so horribly sad, a terribly empty feeling, felt like crying my heart out. Home is like the end of the world. —21.1: Tried to commit suicide. Instead wrote to G. telling him to give me some ideas how to get to America. Feeling just frightful, feel dead. —27.1: No feelings at all. —30.1: Have a mad desire to go really common, lipstick, scarlet nails and with as little clothes as possible.

This occurs when an individual travels or wanders, either in a seemingly purposeful or bewildered fashion, without knowing who they are. Dissociative fugue involves amnesia of a person’s entire identity or for other important autobiographical information.

Another salient difference from Stengel's day is that the fugue state must not due to a general medical condition, like temporal lobe epilepsy.

References

Stengel, E. (1941). On the Aetiology of the Fugue States The British Journal of Psychiatry, 87 (369), 572-599 DOI: 10.1192/bjp.87.369.572

Stengel, E. (1943). Further Studies on Pathological Wandering (Fugues with the Impulse to Wander) The British Journal of Psychiatry, 89 (375), 224-241 DOI: 10.1192/bjp.89.375.224

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.